The aging population and increase of ambulatory surgeries have greatly increased strain on surgical and post-surgical staff that decreases the safety of care. Our overall goal is to find ways to decrease the time of anesthetic recovery to allow for more efficient post-surgical treatment. The specific aims of this study were to assess the correlations between neurocognitive recovery measures of attention and vigilance to brain dynamics. We analyzed reaction time via auditory psychomotor vigilance testing (aPVT) testing and the Richmond agitation-sedation scale (RASS) scores in 145 patients prior to and preceding surgery. Intraoperative electroencephalogram was also recorded for 115 of those patients. Data was analyzed to associate aPVT performance to recovery time and intraoperative brain dynamics. We found an association coefficient between reaction time and RASS recovery of 0.022 (p-value = 0.0001) showing a significant association. Further, we found age to be a significant confounding variable (p=0.04421) and included this in our association model. Lastly, there was no significant association found between intraoperative burst suppression and reaction time values (p=0.497). Overall, aPVT was found to be a robust test to assess recovery timeline in peri-operative anesthesia care unit patients. These results highlighted the potential use of an objective metric to track neurocognitive recovery after anesthesia, especially in elderly patients undergoing surgery.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21680号 / 医博第4486号 / 新制||医||1036(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 村井 俊哉, 教授 松原 和夫 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

New optical technologies were developed to continuously measure cerebral blood flow (CBF) and oxygen metabolism (CMRO2) non-invasively through the skull. Methods and devices were created to improve the performance of near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) for use in experimental animals and humans. These were employed to investigate cerebral metabolism and cerebrovascular reactivity under different states of anesthesia and during models of pathological states. Burst suppression is a brain state arising naturally in pathological conditions or under deep general anesthesia, but its mechanism and consequences are not well understood. Electroencephalography (EEG) and cortical hemodynamics were simultaneously measured in rats to evaluate the coupling between cerebral oxygen metabolism and neuronal activity in the burst suppressed state. EEG bursts were used to deconvolve NIRS and DCS signals into the hemodynamic and metabolic response function for an individual burst. This response was found to be similar to the stereotypical functional hyperemia evoked by normal brain activation. Thus, spontaneous burst activity does not cause metabolic or hemodynamic dysfunction in the cortex. Furthermore, cortical metabolic activity was not associated with the initiation or termination of a burst. A novel technique, time-domain DCS (TD-DCS), was introduced to significantly increase the sensitivity of transcranial CBF measurements to the brain. A new time-correlated single photon counting (TCSPC) instrument with a custom high coherence pulsed laser source was engineered for the first-ever simultaneous measurement of photon time of flight and DCS autocorrelation decays. In this new approach, photon time tags are exploited to determine path-length-dependent autocorrelation functions. By correlating photons according to time of flight, CBF is distinguished from superficial blood flow. Experiments in phantoms and animals demonstrate TD-DCS has significantly greater sensitivity to the brain than existing transcranial techniques. Intracranial pressure (ICP) modulates both steady-state and pulsatile CBF, making CBF a potential marker for ICP. In particular, the critical closing pressure (CrCP) has been proposed as a surrogate measure of ICP. A new DCS device was developed to measure pulsatile CBF non-invasively. A novel method for estimating CrCP and ICP from DCS measurement of pulsatile microvascular blood flow in the cerebral cortex was demonstrated in rats. / 2018-03-08T00:00:00Z

Abstract The purpose of the present study was to gain more insight into the blood oxygen level-dependent (BOLD)-contrast functional MRI (fMRI) in the brain and its connection to EEG, both in global and local scales of their temporal and spatial relations. BOLD signal changes were studied during hyperventilation (HV) induced EEG reactivity of intermittent rhythmic delta activity (IRDA). The BOLD signal in gray matter decreased 30% more in subjects with IRDA (N = 4) than in controls (N = 4), during the first two minutes of HV. This difference disappeared during IRDA in EEG. BOLD signal changes may provide additional information about dynamic hemodynamic changes relative to HV induced EEG reactivity. BOLD signal changes were investigated during sudden deepening of thiopental anesthesia into EEG burst-suppression level in pigs (N = 5). Positive (6–8%) or negative (-3– -8%) group average BOLD signal changes correlated to the thiopental bolus injection were seen. Positive and negative responses covered 1.6% and 2.3% of the brain voxels, respectively. BOLD signal changes in brain are associated with sudden deepening of thiopental anesthesia into EEG burst-suppression level, but they are spatially inconsistent and scarce. Somatosensory BOLD response was studied in brain before and after globally induced methotrexate (MTX) exposition in pigs (N = 4). After the MTX exposure, reduced (from 2–4% to 0–1%) or negative (-2% to -3%) BOLD responses were detected. Somatosensory BOLD-contrast response shows a slight difference in brain before and after globally induced MTX exposition. An experimental epilepsy model for development of simultaneous EEG and BOLD-contrast fMRI in the localization of epilepsy was developed and tested. Dynamic penicillin induced local epilepsy was applied in deep isoflurane anesthesia in pigs (N = 6). Relatively high (10–20%) and localized BOLD signal increase was found. The dynamic penicillin induced focal epilepsy model in deep isoflurane anesthesia with simultaneous EEG and BOLD-contrast fMRI is feasible for the development of these methods for localization of epileptic focus or foci. In conclusion, with careful experimental design and analysis, BOLD-contrast fMRI with EEG provides a potential tool for monitoring and localising functional changes in the brain.

Abstract Several anaesthetics are able to induce a burst-suppression (B-S) pattern in the electroencephalogram (EEG) during deep levels of anaesthesia. A burst-suppression pattern consists of alternating high amplitude bursts and periods of suppressed background activity. All monitors measuring the adequacy of anaesthesia recognize the EEG B-S as one criterion. A better understanding of EEG burst-suppression is important in understanding the mechanisms of anaesthesia. The aim of the study was to acquire a more comprehensive understanding of the function of neural pathways during deep anaesthesia. The thesis is comprised of four prospective clinical studies with EEG recordings from 64 patients, and of one experimental study of a porcine model of epilepsy with EEG registrations together with BOLD fMRI during isoflurane anaesthesia (II). In study I, somatosensory cortical evoked responses to median nerve stimulation were studied under sevoflurane anaesthesia at EEG B-S levels. In study III, The EEGs of three Parkinson`s patients were observed to describe the characteristics of B-S during propofol anaesthesia using scalp electrodes and depth electrodes in the subthalamic nucleus. In study IV, EEG topography was observed in 20 healthy children under anaesthesia mask induction with sevoflurane. Twenty male patients were randomized to either controlled hyperventilation or spontaneous breathing groups for anaesthesia mask induction with sevoflurane in study V. EEG alterations in relation to haemodynamic responses were examined in studies IV and V. Somatosensory information reached the cortex even during deep anaesthesia at EEG burst-suppression level. Further processing of these impulses in the cortex was suppressed. The EEG slow wave oscillations were synchronous over the entire cerebral cortex, while spindles and sharp waves were produced by the sensorimotor cortex. The development of focal epileptic activity could be detected as a BOLD signal increase, which preceded the EEG spike activity. The epileptogenic property of sevoflurane used at high concentrations especially during hyperventilation but also during spontaneous breathing together with heart rate increase, was confirmed in healthy children and male. Spike- and polyspike waveforms concentrated in a multifocal manner frontocentrally. / Tiivistelmä Useat anestesia-aineet pystyvät aiheuttamaan aivosähkökäyrän (EEG) purskevaimentuman syvän anestesian aikana. Purskevaimentuma koostuu EEG:n suuriamplitudisten purskeiden sekä vaimentuneen taustatoiminnan vaihtelusta. Kaikkien anestesian syvyyttä mittaavien valvontalaitteiden toiminta perustuu osaltaan EEG:n purskevaimentuman tunnistamiseen. Tämän ilmiön parempi tunteminen on tärkeää anestesiamekanismien ymmärtämiseksi. Tutkimuksen päämääränä oli saada kattavampi käsitys hermoratojen toiminnasta syvässä anestesiassa. Väitöskirjatyö koostuu neljästä prospektiivisesta yhteensä 64 potilaan EEG-rekisteröinnit sisältävästä tutkimuksesta sekä yhdestä kokeellisen epilepsiatutkimuksen koe-eläintyöstä, jossa porsailla käytettiin isofluraanianestesiassa sekä EEG-rekisteröintejä sekä että magneettikuvantamista (fMRI) samanaikaisesti (II). Ensimmäisessä osatyössä tutkittiin keskihermon stimulaation aiheuttamia somatosensorisia herätepotentiaaleja aivokuorella EEG:n purskevaimentumatasolla sevofluraanianestesian aikana. Kolmannessa osatyössä selvitettiin propofolianestesian aiheuttamaa EEG:n purskevaimentumaa kolmelta Parkinsonin tautia sairastavalta potilaalta käyttäen sekä pintaelektrodien että subtalamisen aivotumakkeen syväelektrodien rekisteröintejä. Neljännessä osatyössä tutkittiin EEG:n topografiaa 20:llä terveeellä lapsella indusoimalla anestesia sevofluraanilla. Kaksikymmentä miespotilasta nukutettiin sevofluraanilla ja heidät satunnaistettiin joko kontrolloidun hyperventilaation tai spontaanin hengityksen ryhmiin osatyössä V. EEG-muutoksia sekä niiden yhteyttä verenkiertovasteisiin selviteltiin molemmissa osatöissä IV ja V. Omasta kehosta tuleviin tuntoärsykkeisiin liittyvä somatosensorinen informaatio saavutti aivokuoren myös syvässä EEG:n purskevaimentumatasoisessa anestesiassa. Impulssien jatkokäsittely aivokuorella oli kuitenkin estynyt. EEG:n hidasaaltotoiminta oli synkronista koko aivokuoren alueella, sen sijaan unisukkulat ja terävät aallot paikantuivat sensorimotoriselle aivokuorelle. Paikallisen epileptisen toiminnan kehittyminen oli mahdollista havaita jo ennen piikikkäiden EEG:n aaltomuotojen ilmaantumista edeltävänä BOLD-ilmiöön liittyvänä aivoverenkierron lisääntymisenä. Sevofluraanin epileptogeenisyys varmistui erityisesti hyperventilaation, mutta myös spontaanin hengityksen yhteydessä ja näihin liittyi sykkeen nousu sekä terveillä lapsilla että miehillä. Piikkejä ja monipiikkejä käsittävien aaltomuotojen keskittymistä esiintyi otsalohkon keskialueilla.

La spectroscopie proche infrarouge fonctionnelle (SPIRf) est une technique de neuro-imagerie noninvasive permettant de mesurer les changements de concentration d’hémoglobine oxygéné (Δ[HbO]) et désoxygéné (Δ[HbR]). Au cours des deux dernières décennies, notre groupe (et d’autres) ont combiné la SPIRf avec l'électroencéphalographie (EEG) pour effectuer des enregistrements chez des patients avec épilepsie réfractaire afin d’évaluer son potentiel comme 1) technique de cartographie cérébrale noninvasive (par exemple, localisation des aires impliquées dans le langage et localisation du foyer épileptique) et 2) comme approche noninvasive pour étudier le couplage neurovasculaire pendant les pointes épileptiques interictales ainsi que lors des crises épileptiques. Malgré des résultats prometteurs, de nombreux enjeux demeurent avant que la EEG-SPIRf puisse être implantée en pratique clinique. En effet, l’installation de l’équipement prend encore trop de temps, l’obtention de signaux de qualité nécessite encore une surveillance serrée et un certain inconfort apparaît au fur et à mesure que les enregistrements progressent dans le temps. C’est d’ailleurs pourquoi les enregistrements EEG-SPIRf ont, jusqu’à maintenant, été généralement de courte durée (c. à d. rarement plus de deux heures) avec une couverture limitée du cortex cérébral (c. à d. généralement une ou deux aires corticales) et dans un milieu contrôlé de recherche (plutôt qu’au chevet dans un milieu clinique). Compte tenu de son potentiel clinique, il y a lieu de poursuivre les efforts pour développer la EEG-SPIRf pour usage clinique. Notamment, un grand potentiel est pressenti pour la EEG-SPIRf aux soins intensifs neurologiques. D’une part, les patients qui y sont admis étant souvent comateux et/ou sous sédation, l’inconfort relié au port d’électrodes et d’optodes n’est plus en enjeu. D’autre part, ces patients présentent généralement des pathologies graves souvent associées à des anomalies épileptiformes fréquentes à l’EEG (décharges périodiques, crises subcliniques, état de mal non convulsif) dont l’impact hémodynamique sur cerveau tout comme leur prise en charge demeurent controversés. Les techniques actuellement utilisées aux soins intensifs (moniteur de pression intracrânienne, sonde de saturation veineuse jugulaire en oxygène, doppler transcrânien, EEG seul sans SPIRf) présentant des limitations, l’ajout d’une composante de SPIRf à l’EEG permettrait possiblement d’élucider l’impact de certaines de ces anomalies épileptiformes, guider leur traitement et en améliorer leur surveillance. Ainsi, cette thèse visait à 1) développer et valider un système d’EEG-SPIRf compact, sans fil et couvrant toute la tête, destinée à une surveillance à long terme de patients souffrant de divers troubles neurologiques; 2) évaluer la faisabilité et le potentiel d’une surveillance vidéo-EEG-SPIRf (vEEG-SPIRf) à long terme auprès de patients comateux admis aux soins intensifs neurologiques présentant des décharges périodiques, des crises ou un patron électrophysiologique de bouffées-suppression; et 3) étudier la dynamique neurovasculaire associée à l'état de mal épileptique non convulsif chez des patients comateux. La première et la deuxième partie du projet décrivent le développement et la validation d'un système EEG-SPIRf hybride et de "casques" EEG-SPIRf personnalisés destinés à surveiller l'hémodynamique corticale entière chez les patients neurologiques. Nous avons d'abord démontré sa performance globale chez des participants sains effectuant deux tâches cognitives spécifiques (c.-à-d. des tâches linguistiques et visuelles) en position assise (pour la première) et en pédalant sur une bicyclette (pour la seconde). Les mesures électrophysiologiques et hémodynamiques ont été validées à l'aide de deux systèmes commerciaux et ont montré, chez tous les participants, une sensibilité et une spécificité spatiotemporelle élevées. Nous avons ensuite démontré le potentiel clinique de notre système chez quatre patients souffrant de divers troubles neurologiques (par exemple, épilepsie réfractaire et maladies vasculaires cérébrales). Nous avons ainsi réalisé avec succès des enregistrements prolongés vEEG-SPIRf au chevet de tous ces patients et observé des changements hémodynamiques cliniquement pertinents et en concordance avec d’autres modalités de neuro-imagerie fonctionnelle. Une originalité particulière de ce projet réside dans sa capacité à "personnaliser" une technique d’imagerie fonctionnelle prometteuse à un environnement clinique (c.-à-d., à l’étage de neurologie et à l’unité de soins intensifs dans notre cas). Cette étude est la première à rapporter avec succès des changements hémodynamiques sur l’ensemble du cortex chez des patients neurologiques à l'aide d’une surveillance vEEG-SPIRf prolongée au chevet. Par la suite, nous avons évalué la faisabilité de la surveillance vEEG-SPIRf à long terme dans un environnement plus ardu : les soins intensifs neurologiques. Nous avons réalisé avec succès de multiples sessions de surveillance vEEG-SPIRf de très longue durée auprès de 11 patients comateux présentant différentes anomalies épileptiformes. Une augmentation significative de [HbO] et une diminution de [HbR] était présentes lors des crises. De plus, ces changements étaient relativement proportionnels à la durée des crises. Bien qu’elles étaient de moins grande amplitude, de similaires Δ[HbO] et de Δ[HbR] était présents durant les bouffées lors de patrons de bouffées-suppression et lors de décharges périodiques de basses fréquences (i.e., < 2Hz). Finalement, dans une étude subséquente, nous avons exploré l'hémodynamique corticale chez 11 patients comateux en état de mal épileptique non convulsif. Nous avons observé dans la majorité des cas, une augmentation de [HbO], du volume sanguin cérébral et du débit sanguin cérébral, mais avec des changements variables de [HbR] lors de courtes crises (inférieure à 100s). Cependant, lors de longues crises (plus de 100s), une augmentation de [HbR] était observée. Ces résultats préliminaires suggèrent que les mécanismes de couplage neurovasculaire pendant l’état de mal épileptique peuvent être dysfonctionnels chez certains patients et induire un état hypoxique, notamment lors de crises prolongées. En conclusion, les observations rapportées dans cette thèse confirment le potentiel clinique de la vEEG-SPIRf chez l'adulte, notamment pour la surveillance des patients admis aux soins intensifs neurologiques à haut risque de décharges épileptiformes. La poursuite de son développement pourrait éventuellement fournir aux neurologues et intensivistes un autre outil de surveillance neurologique. / Functional near-infrared spectroscopy (fNIRS) is a noninvasive neuroimaging technique that measures concentration changes in oxy- and deoxyhemoglobin (Δ[HbO] and Δ[HbR]) associated with brain activity. Over the past two decades, our group (and others) have combined fNIRS with electroencephalography (EEG) to record patients with refractory epilepsy and evaluate its potential as 1) a noninvasive brain mapping technique (e.g., language area localization and localization of epileptic foci) and 2) as a noninvasive approach to study neurovascular coupling during interictal spikes as well as during seizures. Despite promising results, many challenges remain before the EEG-fNIRS can be implemented in clinical practice. Indeed, installing the equipment still takes too much time, obtaining and maintaining good signal quality still requires close monitoring, and the appearance of discomfort as the recordings progress in time. For those reasons, EEG-fNIRS recordings to date have generally been of short duration (i.e., rarely more than two hours) with limited coverage of the cerebral cortex (i.e., typically one or two cortical areas) and in a controlled research setting (rather than at the bedside in a clinical setting). Given its clinical potential, there is a need for continued efforts to develop fNIRS-EEG for clinical use. In particular, fNIRS-EEG has great potential in neurological intensive care. On the one hand, since patients admitted to the ICU are often comatose and/or sedated, the discomfort of wearing electrodes and optodes is no longer an issue. On the other hand, these patients generally present serious pathologies often associated with frequent epileptiform abnormalities on the EEG (periodic discharges, nonconvulsive seizures and status) whose hemodynamic impact on the brain, as well as their management remain controversial. The techniques currently used in intensive care units (intracranial pressure monitor, jugular venous oxygen saturation probe, transcranial Doppler, EEG alone without fNIRS) have limitations. Adding an fNIRS component to the EEG could perhaps elucidate the impact of some of these epileptiform abnormalities, guide their treatment and improve their monitoring. Thus, this thesis aimed to 1) develop and validate a compact, wireless, whole-head EEG-fNIRS system for long-term monitoring of patients with various neurological disorders; 2) to evaluate the feasibility and potential of long-term video EEG-fNIRS (vEEG-fNIRS) monitoring of comatose patients admitted to the neurological intensive care unit with periodic discharges, seizures or an electrophysiological pattern of burst-suppression; and 3) to study the neurovascular dynamics associated with nonconvulsive status epilepticus in comatose patients. The first and second parts of the project describe the development and validation of a hybrid EEG-fNIRS system and personalized EEG-fNIRS "caps" to monitor whole cortical hemodynamics in neurological patients. We first demonstrated its overall performance in healthy participants performing two specific cognitive tasks (i.e., language and visual tasks) while sitting (for the former) and pedalling a bicycle (for the latter). Electrophysiological and hemodynamic measurements were validated using two commercial systems and showed, in all participants, high sensitivity and spatiotemporal specificity. We then demonstrated the clinical potential of our system in four patients suffering from various neurological disorders (e.g., refractory epilepsy and cerebrovascular diseases). We successfully performed prolonged vEEG-fNIRS recordings at the bedside of all these patients and observed clinically relevant hemodynamic changes* in agreement with other functional neuroimaging modalities. A particular originality of this project is its ability to "customize" a promising functional imaging technique specific clinical settings (i.e., neurology ward, epilepsy monitoring unit, and intensive care unit in our case). This study is the first to successfully report hemodynamic changes across the cortex in neurological patients using extended bedside vEEG-fNIRS monitoring. Subsequently, we evaluated the feasibility of long-term vEEG-fNIRS monitoring in a more challenging environment: the neurological intensive care unit. We successfully performed multiple sessions of very long-term vEEG-fNIRS monitoring in 11 comatose patients with different epileptiform abnormalities. During seizures, a significant increase in [HbO] and a decrease in [HbR] were present. Moreover, these changes were relatively proportional to the duration of the seizures. Although they were of lesser magnitude, similar changes in [HbO] and [HbR] were present during bursts in burst-suppression patterns and with low-frequency (i.e., < 2Hz) periodic discharges. Finally, in a subsequent study, we explored cortical hemodynamics in 11 comatose patients in nonconvulsive status epilepticus. We observed in the majority of cases an increase in [HbO], CBV and CBF, but with variable changes in [HbR] during short seizures (less than 100s). However, during prolonged seizures (more than 100s), an increase in [HbR] was seen. These preliminary results suggest that neurovascular coupling mechanisms during status epilepticus may be dysfunctional in some patients and induce a hypoxic state, especially during protracted seizures. In conclusion, the observations reported in this thesis confirm the clinical potential of vEEG-fNIRS in adults, especially for monitoring patients admitted to neurological intensive care units at high risk of epileptiform discharges. Further development could eventually provide neurologists and intensivists with another tool for neurological monitoring.